Simon’s two-stage designs are widely used in cancer phase II clinical trials for assessing the efficacy of a new treatment. However in practice, the actual sample size for the second stage is often different from the planned sample size, and the original inference procedure is no longer valid. Previous work on this problem has certain limitations in computation. In this paper, we attempt to maximize the unconditional power while controlling for the type I error for the modified second stage sample size. A normal approximation is used for computing the power, and the numerical results show that the approximation is accurate even under small sample sizes. The corresponding confidence intervals for the response rate are constructed by inverting the hypothesis test, and they have reasonable coverage while preserving the type I error.
Copyright © 2015 John Wiley & Sons, Ltd.

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The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months’ duration.
In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 μg/kg to 10 μg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417.
Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events.
In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia.
Amgen Inc.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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Early recurrence is the major obstacle for improving the outcome of patients with hepatocellular carcinoma (HCC). Therefore, identifying key molecules contributing to early HCC recurrence can enable the development of novel therapeutic strategies for the clinical management of HCC. Epithelial cell transforming sequence 2 (ECT2) has been implicated in human cancers, but its function in HCC is largely unknown.
ECT2 expression was studied by microarrays, immunoblotting and immunohistochemistry in human HCC samples. siRNA- and lentiviral vector-mediated knockdown were employed to decipher the molecular functions of ECT2.
The upregulation of ECT2 is significantly associated with early recurrent HCC disease and poor survival. Knockdown of ECT2 markedly suppressed Rho GTPases activities, enhanced apoptosis, attenuated oncogenicity and reduced the metastatic ability of HCC cells. Moreover, knockdown of ECT2 or Rho also suppressed ERK activation, while the silencing of Rho or ERK led to a marked reduction in cell migration. Stable knockdown of ECT2 in vivo resulted in significant retardation of tumour growth and the suppression of ERK activation. High expression of ECT2 correlates with high ERK phosphorylation and poor survival of HCC patients. Furthermore, ECT2 enhances the expression and stability of RACGAP1, accelerating ECT2-mediated Rho activation to promote metastasis.
ECT2 is closely associated with the activation of the Rho/ERK signalling axis to promote early HCC recurrence. In addition, ECT2 can crosstalk with RACGAP1 to catalyse the GTP exchange involved in Rho signalling to further regulate tumour initiation and metastasis.
Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Aging is a complex phenomenon leading to numerous changes in the physiological systems of the body. One of the most important changes, called immunosenescence, occurs in the immune system. Immunosenescence covers changes in the innate and the adaptive immune systems and is associated with a low-grade inflammation called inflammaging. Aging, likely via inflammaging, is also associated with the emergence of chronic diseases including cardiovascular and neurodegenerative diseases, cancer, and diabetes mellitus type 2. The origin of this inflammaging is not known with certainty, but several concurrent contributing factors have been suggested, such as aging-associated changes in the innate and adaptive immune response, chronic antigenic stimulation, the appearance of endogenous macromolecular changes, and the presence of senescent cells exhibiting a senescence-associated secretory phenotype. A better understanding of the multiple biological phenomena leading to these diseases via the immunosenescence associated with inflammaging provides a powerful target for interventions to increase the healthspan of elderly subjects.

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Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases.Cell Death and Differentiation advance online publication, 22 April 2016; doi:10.1038/cdd.2016.37.

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